Substitution profile of Δ9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Δ9-tetrahydrocannabinol

Abstract

Rationale Preclinical evidence suggests that non-cannabinoid neurotransmitter systems are involved in the behavioral and physiological effects of cannabinoids, but relatively little research has been conducted in humans. Objectives The aims of this study were to assess whether oral Δ 9 -tetrahydrocannabinol (Δ 9 -THC) would function as a discriminative stimulus in humans and to examine the substitution profile of drugs acting at opioid, GABA, and dopamine systems. Methods Healthy subjects who reported moderate cannabis use were enrolled. Subjects learned to identify when they received oral 25 mg Δ 9 -THC or placebo under double-blind conditions. Once subjects acquired the discrimination (i.e., ≥80% drug-appropriate responding for four consecutive sessions), multiple doses of Δ 9 -THC, the GABA A positive modulator triazolam, the µ-opioid agonist hydromorphone and the dopamine reuptake inhibitor methylphenidate were tested to determine if they shared discriminative-stimulus effects with the training dose of Δ 9 -THC. Results Eight subjects (N=8) accurately discriminated Δ 9 -THC and completed the study. The training dose of Δ 9 -THC functioned as a discriminative stimulus and produced prototypical subject-rated drug effects. All of the drugs Psychopharmacology (2009) 203:241-250 DOI 10.1007/s00213-008-1393 This research and the preparation of this manuscript were supported by grants from the National Institute on Drug Abuse (K01 DA018772) and the University tested produced significant effects on the self-report questionnaires, but only Δ 9 -THC substituted for the training dose. Conclusion These results suggest that the discriminativestimulus effects of Δ 9 -THC in humans are not directly mediated through central neurotransmitter systems acted upon by the drugs tested in this study.

Interactions betweenμ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

“…Opioid receptor agonists and cannabinoid receptor agonists individually can have robust and pharmacologically distinct discriminative stimulus effects. m-Opioid receptor agonists (e.g., morphine and hydromorphone) fail to occasion drugappropriate responding in rhesus monkeys (Wiley et al, 1995a;McMahon, 2006;Li et al, 2008) or humans (Lile et al, 2009) discriminating D 9 -THC. Similarly, D 9 -THC does not occasion drug-appropriate responding in rhesus monkeys discriminating morphine (Li et al, 2008).…”

Substitution Profile of the Cannabinoid Agonist Nabilone in Human Subjects Discriminating Δ9-Tetrahydrocannabinol

“…The drug-discrimination task was completed only 3, 4, and 5 hours after drug administration because of the slow onset (3-4 hours) of the effects of $ 9 -THC observed in our initial study in which drug discrimination procedures with $ 9 -THC were established. 36,40 The Multiple-Choice Procedure was completed at the end of the 5-hour assessment. Except for physiological assessments, data were collected on an Apple Macintosh computer (Apple Computer, Inc, Cupertino, Calif ).…”

“…Well-established drug-discrimination procedures 36 were used to teach subjects to discriminate between a BDrug X[ condition (ie, 25 mg $ 9 -THC) and a BNot Drug X[ condition (ie, placebo).…”

“…35 Methylphendiate was tested as a negative control because it does not bind cannabinoid receptors, and previous studies have demonstrated that it does not engender $ 9 -THCY like discriminative-stimulus effects and produces a pattern of behavioral and physiological responses that differs from that of $ 9 -THC. 36 …”

JWH-018 and JWH-073: Δ9-Tetrahydrocannabinol-Like Discriminative Stimulus Effects in Monkeys

“…Typically any one of a variety of species, including pigeons, mice, rats, monkeys, and humans, responds on one manipulandum after receiving ⌬ 9 -THC and another after receiving vehicle (Henriksson et al, 1975;Wiley et al, 1993;McMahon, 2006McMahon, , 2008Lile et al, 2009). Once adequately trained, subjects respond on the ⌬ 9 -THC-associated manipulandum after receiving ⌬ 9 -THC or other CB 1 receptor agonists and, in general, the vehicleappropriate manipulandum after receiving noncannabinoids.…”